The present invention relates to a production method of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester. 7-Azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1xcex1,5xcex1,6xcex1)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate, obtained by the present invention, is useful as a synthetic intermediate for GS4104 represented by the following formula. GS4104 is a compound under development as a novel agent for the prophylaxis and treatment of influenza based on the action to prevent viral growth by inhibiting neuraminidase present on the surface of influenza virus (hereinafter to be generally referred to as anti-influenza drug) [see Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); Journal of American Chemical Society (J. Am. Chem. Soc.), vol. 119, p. 681 (1997)]. 
As a conventional synthetic method of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1xcex1,5xcex1,6xcex1)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate, a synthetic method wherein shikimic acid is used as a starting material [see Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); WO 99/14185; WO 98/07685], and a synthetic method wherein guinic acid is used as a starting material [see Journal of American Chemical Society (J. Am. Chem. Soc.), vol. 119, p. 681 (1997)] and the like are known.
The shikimic acid and quinic acid used as a starting material for the conventional synthetic method of ethyl (1xcex1,5xcex1,6xcex1)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate are produced in less amounts and expensive. All the above-mentioned methods require many reaction steps. As widely known, influenza often becomes an epidemic disease worldwide, and an anti-influenza drug is required to be economical and supplied in a large amount. The above-mentioned production methods are not necessarily advantageous as a production method of the intermediate for GS4104 under development as an anti-influenza drug from the industrial viewpoint, and there is a demand for a synthetic method capable of economical production in a large amount.
It is therefore an object of the present invention to provide a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1xcex1,5xcex1,6xcex1)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate, useful as a synthetic intermediate for GS4104 under development as an anti-influenza drug, economically, industrially advantageously and efficiently in a large amount.
According to the present invention, the above-mentioned objects can be achieved by providing
1) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (VII) 
wherein R1 is an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents and R3 is an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an alkenyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents [hereinafter to be abbreviated as 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII)], which comprises the steps of
(A) reacting a 5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of the formula (I) 
wherein R1 is as defined above [hereinafter to be abbreviated as epoxide (I)] with an amine of the formula (II)
R2NH2xe2x80x83xe2x80x83(II)
wherein R2 is a hydrogen atom, an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an alkenyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents [hereinafter to be abbreviated as amine (II)] to give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of the formula (III) 
wherein R1 and R2 are as defined above [hereinafter to be abbreviated as aminodiol (III)],
(B) reacting the obtained aminodiol (III) with a sulfonylating agent in the presence of a base to give a 5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of the formula (IV) 
wherein R1 and R2 are as defined above and A is an organic sulfonyl group [hereinafter to be abbreviated as azabicyclohept-2-ene (IV)],
(C) reacting the obtained azabicyclohept-2-ene (IV) with an alcohol of the formula (V)
R3OHxe2x80x83xe2x80x83(V)
wherein R3 is as defined above [hereinafter to be abbreviated as alcohol (V)] in the presence of a Lewis acid to give a 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (VI) 
wherein R1, R2 and R3 are as defined above [hereinafter to be abbreviated as azabicyclohept-3-ene (VI)], and
(D) when R2 is an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an alkenyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents, eliminating the 7-position substituent R2 of the obtained azabicyclohept-3-ene (VI),
(2) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII), which comprises the steps of
(A) reacting epoxide (I) with amine (II) to give aminodiol (III),
(B) protecting an amino group of the obtained aminodiol (III) to give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of the formula (VIII) 
wherein R1 and R2 are as defined above and R4 is an amino-protecting group [hereinafter to be abbreviated as aminodiol (VIII)],
(C) reacting the obtained aminodiol (VIII) with a sulfonylating agent in the presence of a base to give a 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of the formula (IX) 
wherein R1, R2 and R4 are as defined above and A is an organic sulfonyl group [hereinafter to be abbreviated as disulfonate (IX)],
(D) removing the amino-protecting group from the obtained disulfonate (IX) to give a 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of the formula (X) 
wherein R1, R2 and A are as defined above [hereinafter to be abbreviated as disulfonate (X)],
(E) reacting the obtained disulfonate (X) with a base to give azabicyclohept-2-ene (IV),
(F) reacting the obtained azabicyclohept-2-ene (IV) with alcohol (V) in the presence of a Lewis acid to give azabicyclohept-3-ene (VI), and
(G) when R2 is an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an alkenyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents, eliminating the 7-position substituent R2 from the obtained azabicyclohept-3-ene (VI),
(3) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII), which comprises eliminating the 7-position substituent R2xe2x80x2, from a 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (VIxe2x80x2) 
wherein R2xe2x80x2, is an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an alkenyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents, and R1 and R3 are as defined above,
(4) a production method of azabicyclohept-3-ene (VI), which comprises reacting azabicyclohept-2-ene (IV) with alcohol (V) in the presence of a Lewis acid,
(5) a production method of azabicyclohept-2-ene (IV), which comprises reacting aminodiol (III) with a sulfonylating agent in the presence-of a base,
(6) a production method of azabicyclohept-2-ene (IV), which comprises reacting disulfonate (X) with a base,
(7) a production method of azabicyclohept-2-ene (IV), which comprises (A) protecting an amino group of aminodiol (III) to give aminodiol (VIII),
(B) reacting the obtained aminodiol (VIII) with a sulfonylating agent in the presence of a base to give disulfonate (IX),
(C) removing the amino-protecting group of the obtained disulfonate (IX) to give disulfonate (X), and
(D) reacting the obtained disulfonate (X) with a base, and
(8) a production method of aminodiol (III), which comprises reacting epoxide (I) with amine (II).
In the above-mentioned formulas, the alkyl group represented by R1, R2 and R3 is a straight chain or branched chain alkyl group preferably having 1 to 10, more preferably 1 to 6 carbon atoms. Examples thereof include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, 1-ethylpropyl group, hexyl group and the like. These alkyl groups may have substituents and examples of the substituent include alkoxyl group preferably having 1 to 10, more preferably 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, butoxy group and the like; halogen atom such as fluorine atom, chlorine atom, bromine atom and the like; cyano group; nitro group; and the like.
The cycloalkyl group represented by R1, R2 and R3 is cycloalkyl group preferably having 3 to 8 carbon atoms and is exemplified by cyclopentyl group, cyclohexyl group, cyclooctyl group and the like. The aryl group represented by R1, R2 and R3 is aryl group preferably having 6 to 10 carbon atoms, and is exemplified by phenyl group, naphthyl group and the like. The aralkyl group represented by R1, R2 and R3 is aralkyl group wherein the alkyl moiety is alkyl group preferably having 1 to 6 carbon atoms and the aryl moiety has 1 to 3 aryl groups defined above. Examples thereof include benzyl group, diphenylmethyl group, triphenylmethyl group, phenethyl group and the like. These cycloalkyl group, aryl group and aralkyl group may have substituents and examples of the substituent include alkyl group preferably having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group and the like; alkoxyl group preferably having 1 to 6 carbon atoms such as methoxy group, ethoxy group, propoxy group, butoxy group and the like; halogen atom such as fluorine atom, chlorine atom bromine atom and the like; cyano group; nitro group and the like.
The alkenyl group represented by R2 and R3 is a straight chain or branched chain alkenyl group preferably having 2 to 10, more preferably 2 to 6 carbon atoms. Examples thereof include allyl group, isopropenyl group, 2-methylallyl group and the like. These alkenyl groups may have substituents and examples of the substituent include alkoxyl group preferably having 1 to 6 carbon atoms such as methoxy group, ethoxy group, propoxy group, butoxy group and the like; halogen atom such as fluorine atom, chlorine atom, bromine atom and the like; cyano group; nitro group; and the like.
As R2, an aralkyl group optionally having substituents (e.g., benzyl group, diphenylmethyl group) is preferable.
The protecting group of the amino group represented by R4 is free of any particular limitation as long as it is generally used for protecting the amino group, and is exemplified by alkoxycarbonyl group such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-iodoethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-methylthioethoxycarbonyl group, 1,1-dimethylpropyloxycarbonyl group, 1-methyl-1-phenylethoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, cinnamyloxycarbonyl group, 1,1-dimethylpropynyloxycarbonyl group and the like; aralkyloxycarbonyl group such as 9-fluorenylmethoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group and the like; aralkyl group such as benzyl group, 2,4,6-trimethylbenzyl group, p-methoxybenzyl group, 3,5-dimethoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group, o-chlorobenzyl group, p-chlorobenzyl group, o-bromobenzyl group, p-bromobenzyl group, 2,4-dichlorobenzyl group, p-cyanobenzyl group, m-chloro-p-acyloxybenzyl group, 9-anthrylmethyl group, diphenylmethyl group, phenyl(o-nitrophenyl)methyl group, di(2-pyridyl)methyl group, (4-pyridyl)methyl group, triphenylmethyl group and the like; acyl group such as formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, o-nitrophenylacetyl group, p-nitrophenylacetyl group, o-nitrophenoxyacetyl group, p-nitrophenoxyacetyl group, acetoacetyl group, pyridylacetyl group and the like; and the like.
The organic sulfonyl group represented by A is free of any particular limitation as long as it is bonded with an organic group, and is exemplified by alkylsulfonyl group optionally having substituents, arylsulfonyl group optionally having substituents, aralkylsulfonyl group optionally having substituents and the like. The alkyl moiety of the alkylsulfonyl group is alkyl group preferably having 1 to 6 carbon atoms. The aryl moiety of the arylsulfonyl group is, for example, phenyl group. The aryl moiety of the aralkylsulfonyl group is, for example, phenyl group, and the alkyl moiety is alkyl group preferably having 1 to 6 carbon atoms. The alkylsulfonyl group may have substituents, and examples of the substituent include alkoxyl group (alkoxyl group preferably having 1 to 6 carbon atoms), halogen atom, cyano group, nitro group and the like. The arylsulfonyl group and aralkylsulfonyl group may have substituents on the aromatic ring, and examples of the substituent include alkyl group (alkyl group preferably having 1 to 6 carbon atoms), alkoxyl group (alkoxyl group preferably having 1 to 6 carbon atoms), halogen atom, cyano group, nitro group and the like. The organic sulfonyl group represented by A is exemplified by methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group, p-methoxybenzenesulfonyl group, 2,4,6-trimethylbenzenesulfonyl group, benzylsulfonyl group, p-methylbenzylsulfonyl group, trifluoromethanesulfonyl group and the like.
The production method of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) of the present invention is shown in the following scheme, and includes two production methods of route (i) and route (ii), which can be determined as appropriate according to the kind of amine (II) to be used. 
wherein R1, R2, R3, R4 and A are as defined above.
In the following, each step is explained.
(a): step for reacting epoxide (I) with amine (II) to give aminodiol (III)
Examples of the amine (II) include ammonia, methylamine, ethylamine, propylamine, n-butylamine, cyclohexylamine, cyclooctylamine, allylamine, isopropenylamine, aniline, 4-methylphenylamine, benzylamine, benzhydrylamine and the like. Of these, benzylamine and benzhydrylamine are particularly preferable. The amount of the amine (II) to be used is generally preferably 1 to 10-fold moles, particularly preferably 1 to 1.5-fold moles, per 1 mole of epoxide (I).
The reaction can be carried out in the presence or absence of a solvent. The solvent to be used is free of any particular limitation as long as it does not adversely affect the reaction. Examples thereof include aliphatic hydrocarbon such as hexane, heptane, octane and the like; aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; and the like. When a solvent is used, the amount of the solvent to be used is free of any particular limitation, but it is generally preferably 1 to 10-fold weight, more preferably 1 to 3-fold weight, relative to epoxide (I).
The reaction temperature is preferably 20 to 200xc2x0 C., more preferably 50xc2x0 C. to 80xc2x0 C. While the reaction time varies depending on the kind and the amount of epoxide (I), amine (II) and the solvent, it is generally within the range of 1 to 48 hours.
The reaction is carried out by, for example, mixing epoxide (I), amine (II) and a solvent as necessary and stirring the mixture at a given temperature.
The aminodiol (III) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is concentrated, and the obtained concentrate is purified by distillation, column chromatography and the like.
(b): Step for reacting aminodiol (III) with a sulfonylating agent in the presence of a base to give azabicyclohept-2-ene (IV)
Examples of the base include tertiary amine such as trimethylamine, triethylamine, tripropylamine, tributylamine, trioctylamine, pyridine, collidine, lutidine and the like; alkaline metal hydride such as sodium hydride, potassium hydride and the like; alkaline metal carbonate such as sodium carbonate, potassium carbonate and the like; and the like. Of these, triethylamine, pyridine and lutidine are preferable. The amount of the base to be used is preferably 2 to 100-fold moles, more preferably 2 to 25-fold moles, per 1 mole of aminodiol (III).
Examples of the sulfonylating agent include organic sulfonyl halide such as methanesulfonyl chloride, methanesulfonyl fluoride, ethanesulfonyl chloride, ethanesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonyl bromide, benzenesulfonyl fluoride, toluenesulfonyl chloride, toluenesulfonyl bromide, toluenesulfonyl fluoride, p-methoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, benzylsulfonyl chloride, p-methylbenzylsulfonyl chloride, trifluoromethanesulfonyl chloride and-the like; sulfonic anhydride such as methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride and the like; and the like. The amount of the sulfonylating agent to be used is preferably 2 to 10-fold moles, more preferably 2 to 5-fold moles, per 1 mole of aminodiol (III).
The reaction is preferably carried out in a solvent. The solvent to be used is free of any particular limitation as long as it does not adversely affect the reaction. Examples thereof include aliphatic hydrocarbon such as hexane, heptane, octane and the like; aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; and the like. The amount of the solvent to be used is free of any particular limitation, but it is generally preferably 1 to 100-fold weight, more preferably 1 to 10-fold weight, relative to aminodiol (III).
The reaction temperature is preferably xe2x88x9220xc2x0 C. to 1500xc2x0 C., more preferably 10xc2x0 C. to 80xc2x0 C. While the reaction time varies depending on the kind and the amount of aminodiol (III), base, sulfonylating agent and solvent, it is generally within the range of 1 to 48 hours.
The reaction is carried out by, for example, dissolving aminodiol (III) and a base in a solvent, adding a sulfonylating agent and stirring the mixture at a given temperature.
The azabicyclohept-2-ene (IV) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is poured into water, extracted with aliphatic hydrocarbon such as n-hexane and the like, aromatic hydrocarbon such as toluene and the like, halogenated hydrocarbon such as dichloromethane and the like, ether such as diethyl ether, diisopropyl ether and the like; and the like, and the extract is concentrated and the obtained concentrate is purified by distillation, column chromatography and the like.
(c): step for reacting azabicyclohept-2-ene (IV) and alcohol (V) in the presence of Lewis acid to-give azabicyclohept-3-ene (VI)
Examples of the alcohol (V) include primary alcohol such as methanol, ethanol, 1-propanol, 1-octanol, allyl alcohol, benzyl alcohol and the like; secondary alcohol such as isopropanol, 2-butanol, 3-pentanol, cyclopentanol, cyclohexanol and the like. Of these, the use of 3-pentanol as alcohol (V) is particularly preferable from the viewpoint of synthesis of ethyl (1xcex1,5xcex1,6xcex1)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate, which is a synthetic intermediate for GS4104. The amount of the alcohol (V) to be used is preferably 1 to 200-fold moles, more preferably 10 to 100-fold moles, per 1 mole of azabicyclohept-2-ene (IV).
Examples of the Lewis acid include boron trifluoride-etherate, aluminum chloride, zinc chloride, zinc iodide, titanium tetrachloride and the like. The amount of the Lewis acid to be used is preferably 0.1 to 30-fold moles, more preferably 1 to 10-fold moles, per 1 mole of azabicyclohept-2-ene (IV).
The reaction can be carried out in the presence or absence of a solvent. Examples of the solvent to be used is free of any particular limitation as long as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbon such as hexane, heptane, octane and the like; aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, -1,2-dichloroethane and the like; and the like. When a solvent is used, the amount thereof is free of any particular limitation. It is generally preferably 1 to 100-fold weight, more preferably 1 to 10-fold weight relative to azabicyclohept-2-ene (IV).
For efficient progress of the reaction, a base may be also present during the reaction. Examples of the base include amine such as triethylamine, pyridine, collidine, lutidine and the like; alkaline metal hydride such as sodium hydride, potassium hydride and the like; alkaline metal carbonate such as sodium carbonate, potassium carbonate and the like; and the like. When a base is co-used, the amount thereof is free of any particular limitation, but it is preferably 2 to 100-fold moles, more preferably 2 to 25-fold moles, relative to azabicyclohept-2-ene (IV). 10 The reaction temperature is preferably 0-100xc2x0 C., more preferably 10-80xc2x0 C. While the reaction time varies depending on the kind and the amount of azabicyclohept-2-ene (IV), alcohol (V), Lewis acid and solvent, it is generally 0.5 to 10 hours.
The reaction is carried out by, for example, mixing azabicyclohept-2-ene (IV), alcohol (V), Lewis acid and a solvent as necessary and stirring the mixture at a given temperature. When a base is further co-used for the reaction, the base is preferably added after start of stirring as mentioned above. In this case, the given amount of the base may be added at once or added by several-divided portions.
The azabicyclohept-3-ene (VI) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is poured into water, extracted with aliphatic hydrocarbon such as n-hexane and the like, aromatic hydrocarbon such as toluene and the like, ether such as diethyl ether, diisopropyl ether and the like; and the like, and the extract is concentrated and the obtained concentrate is purified by distillation, column chromatography and the like.
When R2 is a hydrogen atom, the objective 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) can be obtained at this stage without performing the next step (d).
(d): step for obtaining 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) by eliminating the 7-position substituent R2 from azabicyclohept-2-ene (VI) The 7-position substituent R2 can be eliminated from azabicyclohept-3-ene (VI) by, for example, a treatment with an acid or according to a known method using catalytic hydrogenation (T. W. Green, xe2x80x9cProtective Groups in organic Synthesis,xe2x80x9d John-Wiley and Sons, New York, pp 218-287 (1981)).
For the treatment with an acid, azabicyclohept-3-ene (VI) is brought into contact with, for example, a solution of hydrogen chloride or hydrogen bromide in alcohol such as ethanol and the like. Examples of the catalytic hydrogenation include a method including reacting azabicyclohept-3-ene (VI) with a hydrogen source such as hydrogen, formic acid and the like in the presence of a catalyst such as Raney-nickel, palladium-carbon and the like.
Particularly, when the 7-position substituent R2 is an aralkyl group, such as benzyl group and diphenylmethyl group, a method for eliminating the 7-position substituent using palladium-carbon as a catalyst and formic acid as a hydrogen source is particularly preferable, because only the 7-position substituent can be selectively eliminated without reducing the double bond of cyclohexene ring. The palladium-carbon to be used here may be those commercially available for hydrogenation, where no limitation is imposed on the amount of palladium to be carried and the like. The weight of palladium-carbon to be used is preferably 0.1 to 10-fold weight, more preferably 0.5 to 3-fold weight, relative to azabicyclohept-3-ene (VI). The amount of the formic acid to be used is preferably 1 to 100-fold moles, more preferably 1 to 10-fold moles, relative to azabicyclohept-3-ene (VI). The reaction is preferably carried out in a solvent. As the solvent, alcohol such as methanol, ethanol and the like; aliphatic hydrocarbon such as hexane, heptane, octane and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like; halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; and the like are exemplified. Of these, aliphatic hydrocarbon such as hexane, heptane, octane and the like; alcohol such as methanol, ethanol and the like are more preferable. The amount of the solvent to be used is free of any particular limitation but it is generally preferably 1 to 100-fold weight, more preferably 1 to 10-fold weight, relative to azabicyclohept-3-ene (VI). The reaction temperature is preferably xe2x88x9250 to 100xc2x0 C., more preferably xe2x88x9220 to 50xc2x0 C.
The 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is neutralized or filtrated, then concentrated, and the obtained concentrate is purified by distillation, column chromatography and the like.
(e): step to protect amino group of aminodiol (III) to give aminodiol (VIII)
As the protecting group used to protect amino group of aminodiol (III), the protecting groups generally used for the protection of amino group can be used. Of these protecting groups, those stable under the reaction conditions, under which to produce disulfonate (IX) in the next step (f), and capable of being removed when the protecting group is to be quickly removed in step (g) to be mentioned below, without impairing other moieties of disulfonate (X) are particularly preferable. Examples of the amino-protecting group include alkoxycarbonyl group such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 1,1-dimethylpropyloxycarbonyl group and the like; aralkyloxycarbonyl group such as p-methoxybenzyloxycarbonyl group and the like. Of these, tert-butoxycarbonyl group is particularly preferable. These amino-protecting groups can be introduced by a known method (T. W. Green, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John-Wiley and Sons, New York, pp 218-287 (1981)). For example, tert-butoxycarbonyl group can be introduced by the use of di-tert-butyl dicarbonate in an amount of 1 to 3-fold moles, more preferably 1 to 1.2-fold moles, relative to-aminodiol (III).
The reaction to protect amino group is preferably carried out in the presence of a solvent. The solvent to be used is free of any particular limitation as long as it does not adversely affect the reaction and examples thereof include halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; aliphatic hydrocarbon such as hexane, heptane, octane and the like; aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; acetonitrile; and the like. The amount of the solvent to be used is free of any particular limitation, but generally it is preferably 1 to 100-fold weight, more preferably 1 to 10-fold weight, relative to aminodiol (III).
The reaction temperature is preferably xe2x88x9220 to 150xc2x0 C., more preferably 20 to 80xc2x0 C.
The aminodiol (VIII) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is poured into water, extracted with aliphatic hydrocarbon such as n-hexane and the like, aromatic hydrocarbon such as toluene and the like, ether such as diethyl ether, diisopropyl ether and the like; and the like, and the extract is concentrated and the obtained concentrate is purified by distillation, column chromatography and the like.
(f): step for reacting aminodiol (VIII) with a sulfonylating agent in the presence of a base to give disulfonate (IX)
As the sulfonylating agent, the compounds recited in the above-mentioned step (b) can be used. The amount of the sulfonylating agent to be used is preferably 2 to 10-fold moles, more preferably 2 to 5-fold moles, per 1 mole of aminodiol (VIII).
Examples of the base include tertiary amine such as trimethylamine, triethylamine, tripropylamine, tributylamine, trioctylamine, pyridine, collidine, lutidine and the like; alkaline metal hydride such as sodium hydride, potassium hydride and the like; alkaline metal carbonate such as sodium carbonate, potassium carbonate and the like; and the like. Of these, triethylamine, pyridine and lutidine are preferable. The amount of the base to be used is preferably 2 to 10-fold moles, more preferably 2 to 5-fold moles, per 1 mole of aminodiol (VIII).
The reaction is preferably carried out in the presence of a solvent. The solvent to be used is free of any particular limitation as long as it is not involved in the reaction. Examples thereof include aliphatic hydrocarbon such as hexane, heptane, octane and the like; aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; and the like. The amount of the solvent to be used is free of any particular limitation but it is generally preferably 1 to 100-fold weight, more preferably 1 to 10-fold weight, relative to aminodiol (VIII).
The reaction temperature is preferably 0-50xc2x0 C., more preferably 10-30xc2x0 C. While the reaction time varies depending on the kind and the amount of aminodiol (VIII), base, sulfonylating agent and solvent, it is generally 1 to 48 hours.
The reaction is preferably carried out by, for example, dissolving aminodiol (VIII) and a base in a solvent, adjusting to a given temperature, adding a sulfonylating agent and stirring the mixture.
The disulfonate (IX) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is poured into water, extracted with aliphatic hydrocarbon such as n-hexane and the like, aromatic hydrocarbon such as toluene and the like, ether such as diethyl ether, diisopropyl ether and the like; and the like, and the extract is concentrated and the obtained concentrate is purified by distillation, column chromatography and the like.
(g): step to remove amino-protecting group from disulfonate (IX) to give disulfonate (X)
The amino-protecting group can be removed from disulfonate (IX) according to a known method (T. W. Green, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John-Wiley and Sons, New York, pp 218-287 (1981)). When the amino-protecting group is tert-butoxycarbonyl group, it can be removed by using trifluoroacetic acid, trimethylbromosilane, trimethyliodosilane and the like and halogenated hydrocarbon such as dichloromethane, chloroform and the like as a solvent in a proportion of 1 to 100-fold weight, preferably 1 to 10-fold weight, relative to disulfonate (IX), at a reaction temperature of 0-50xc2x0 C., preferably 10-30xc2x0 C. The obtained disulfonate (X) can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is poured into water, extracted with aliphatic hydrocarbon such as n-hexane and the like, aromatic hydrocarbon such as toluene and the like, ether such as diethyl ether, diisopropyl ether and the like; and the like, and the extract is concentrated and the obtained concentrate is purified by distillation, column chromatography and the like.
(h): step to react disulfonate (X) with a base to obtain azabicyclohept-2-ene (IV)
Examples of the base include tertiary amine such as trimethylamine, triethylamine, tripropylamine, tributylamine, trioctylamine, pyridine, collidine, lutidine and the like; alkaline metal hydride such as sodium hydride, potassium hydride and the like; alkaline metal carbonate such as sodium carbonate, potassium carbonate and the like; and the like. Of these, triethylamine, pyridine and lutidine are preferable. The amount of the base to be used is preferably 2 to 100-fold moles, more preferably 2 to 25-fold moles, per 1 mole of disulfonate (X).
The reaction is preferably carried out in the presence of a solvent. The solvent to be used is free of any particular limitation as long as it is not involved in the reaction. Examples thereof include aliphatic hydrocarbon such as hexane, heptane, octane and the like; aromatic hydrocarbon such as benzene; toluene, xylene, mesitylene and the like; ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; and the like. The amount of the solvent to be used is free of any particular limitation, and generally it is preferably 1 to 100-fold weight, more preferably 1 to 10-fold weight, relative to disulfonate (X).
The reaction temperature is preferably 0-150xc2x0 C., more preferably 20-80xc2x0 C. While the reaction time varies depending on the kind and the amount of use of disulfonate (X), base and solvent, it is generally 1 to 48 hours.
The reaction is preferably carried out by, for example, dissolving disulfonate (X) and a base in a solvent and stirring the mixture at a given temperature.
The azabicyclohept-2-ene (IV) thus obtained can be purified and separated according to a method generally employed for the purification and separation of organic compounds. For example, the reaction mixture is poured into water, extracted with aliphatic hydrocarbon such as n-hexane and the like, aromatic hydrocarbon such as toluene and the like, ether such as diethyl ether, diisopropyl ether and the like; and the like, and the extract is concentrated and the obtained concentrate is purified by distillation, column chromatography and the like.
The epoxide (I), which is a starting material for the present invention, can be produced as shown in Reference Examples 1-3 to be mentioned below, wherein furan and acrylic acid ester of the formula (XI) 
wherein R1 is as defined above, are subjected to a Diels-Alder reaction in the presence of Lewis acid, such as zinc iodide, zinc chloride, titanium tetrachloride and the like, the obtained compound is reacted with a base such as lithium diisopropylamide, lithium hexamethyldisilazide and the like to perform intramolecular retro-Michael reaction to give dieno alcohol of the formula (XII) 
wherein R1 is as defined above [see Tetrahedron Letters, vol. 23, p. 5299 (1982)], and this dieno alcohol is reacted with peroxide such as magnesium monoperoxyphthalate, peracetic acid, m-chloroperbenzoic acid and the like [see Journal of American Chemical Society (J. Am. Chem. Soc.), vol. 104, p. 7036 (1982)].
According to the method described in Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998), GS4104 can be synthesized from 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII), such as ethyl (1xcex1,5xcex1,6xcex1)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate obtained by the method of the present invention.